Presence of a 34-gene signature is a favorable prognostic marker in squamous non-small cell lung carcinoma.

BACKGROUND: The tumor immune microenvironment is a heterogeneous entity. Gene expression analysis allows us to perform comprehensive immunoprofiling and may assist in dissecting the different components of the immune infiltrate. As gene expression analysis also provides information regarding tumor cells, differences in interactions between the immune system and specific tumor characteristics can also be explored. This study aims to gain further insights in the composition of the tumor immune infiltrate and to correlate these components to histology and overall survival in non-small cell lung cancer (NSCLC). METHODS: Archival tissues from 530 early stage, resected NSCLC patients with annotated tumor and patient characteristics were analyzed using the NanoString nCounter Analysis system. RESULTS: Unsupervised clustering of the samples was mainly driven by the overall level of inflammation, which was not correlated with survival in this patient set. Adenocarcinoma (AD) showed a significantly higher degree of immune infiltration compared to squamous cell carcinoma (SCC). A 34-gene signature, which did not correlate with the overall level of immune infiltration, was identified and showed an OS benefit in SCC. Strikingly, this benefit was not observed in AD. This difference in OS in SCC specifically was confirmed in two independent NSCLC cohorts. The highest correlation between expression of the 34-gene signature and specific immune cell populations was observed for NK cells, but although a plausible mechanism for NK cell intervention in tumor growth could be established in SCC over AD, this could not be translated back to immunohistochemistry, which showed that NK cell infiltration is scarce irrespective of histology. CONCLUSIONS: These findings suggest that the ability of immune cell infiltration and the interaction between tumor and immune cells may be different between AD and SCC histology and that a subgroup of SCC tumors seems more susceptible to Natural Killer cell recognition and killing, whereas this may not occur in AD tumors. A highly sensitive technique like NanoString was able to detect this subgroup based on a 34-gene signature, but further research will be needed to assist in explaining the biological rationale of such low-level expression signatures.

FGFR1, 2 and 3 protein overexpression and molecular aberrations of FGFR3 in early stage non-small cell lung cancer.

This study aimed to determine protein expression levels of fibroblast growth factor receptors (FGFR) 1, 2 and 3 in early stage non-small cell lung cancer (NSCLC). Additionally, a screen to define the frequency of FGFR3-TACC3 translocation and FGFR3 amplification was performed. Archived tissues from 653 NSCLC samples (adenocarcinoma (AC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC)) were analysed with immunohistochemistry (IHC) for expression of FGFR1, 2 and 3. Expression levels of FGFR1, 2 and 3 were correlated with clinicopathological features. The presence of FGFR3-TACC3 translocation was detected by RT-PCR and FGFR3 amplification was detected by fluorescence in situ hybridization. FGFR1, 2 and 3 proteins were highly expressed in 64 (10.6%), 76 (12.9%) and 20 (3.3%) NSCLC tumour samples, respectively. Protein expression of FGFR1 was significantly related to worse overall survival in NSCLC. Furthermore, FGFR1 protein expression was associated with light smoking and histological subtype (AC), FGFR2 protein expression with female gender, younger age, histological subtype (AC) and lower tumour stage, and FGFR3 protein was significantly overexpressed in tumours of older patients and SCC histology. The FGFR3-TACC3 fusion was detected in 3.0% (6/200) of NSCLC samples and the FGFR3 gene was amplified in 4.7% of IHC positive NSCLC samples (2/43). FGFR1, 2 and 3 proteins are expressed in a high number of early stage NSCLC and FGFR1 protein expression may serve as a prognostic biomarker. Recurrent translocations and amplifications in FGFR3 can be found in NSCLC. This study shows that FGFR family members are frequently aberrant in NSCLC and could be interesting therapeutic targets for the treatment of NSCLC.

[Molecular pathology in tumour classification: the present and future molecular revolution]. / Moleculaire pathologie bij tumorclassificatie: heden en toekomst van de moleculaire revolutie.

The way we classify somatic diseases changes rapidly. Whereas at one time examination by the naked eye was used as a guide and then microscopy was used to view a tissue's properties, diseases are increasingly being classified according to their molecular properties. Due to this 'molecular revolution' the diagnostic classification is increasingly predictive. Parallel to this development the boundaries between clinical disciplines are disappearing.

[Task differentiation, in pathology as well]. / Taakherschikking, ook in de pathologie.

The field of clinical pathology, like other medical professions, is becoming more and more complex, leading to a need for subspecialisation and task differentiation. Whereas the deployment of Physician Assistants is common in other specialties, it is still rare in pathology. Although legal regulations state that histopathological diagnoses can only be made by pathologists, this does not mean that Physician Assistants cannot play a role in pathology. Within the legal regulations they can assist in screening cytological specimens and 'simple' histological specimens. They can also assist in the preparation of macroscopical specimens. These not only include specimens such as gallbladders and appendices, but also oncological specimens such as colon carcinoma resection, in which it has been demonstrated that on average, Pathology Assistants find more lymph nodes than pathologists.

Trimodality therapy for superior sulcus tumours: evolution and evaluation of a treatment protocol.

AIM: We studied the clinical outcomes of a trimodality protocol used for the treatment of superior sulcus tumours (SST) in a tertiary referral centre. METHODS: The details of all patients who underwent treatment for a SST between January 2003 and December 2009 were retrospectively analysed. Following pre-treatment staging, all patients underwent concurrent chemoradiotherapy with cisplatin/etoposide, followed by surgery. Outcomes studied were treatment-related complications, pathological response rates, recurrence rates and survival. RESULTS: Fifty-four patients were treated by chemotherapy (cisplatin/etoposide) and concurrent radiotherapy (46-66 Gy) followed by surgical resection. Minimum follow-up was 23 months. No 30-day mortality was observed. A complete (R0) resection was performed in 44 out of 54 patients. None had an R2 resection. Two-year survival was 50% (95%CI: 36.7-63.3). Patients who achieved a pathological complete response (n = 16) had a 2-year survival of 81% (95%CI: 62.1-100.0) versus a 37% 2-year survival (95%CI: 21.5-52.1) in patients with remaining vital tumour in their resection specimens (n = 38; P = 0.003). Five patients developed a local recurrence, and 23 patients a distant metastasis, mainly to the brain (n = 15). Two patients died from causes unrelated to cancer. CONCLUSIONS: Trimodality treatment of SST in accordance to our protocol achieved results comparable to previous reports. Pathological response rates to induction were an important prognostic factor, and distant metastasis remains a major problem.

[Virtual autopsy--why not?]. / Virtuele obductie, waarom niet?

The number of autopsies carried out by pathologists is decreasing. This is worrying, as evaluation has shown 10-20% of autopsies result in findings which could have influenced the course and treatment of the disease if they had been known about in time. Post-mortem imaging or virtual autopsy may be an alternative. However, a number of practical matters have to be taken into consideration before virtual autopsy becomes widely-accepted practice. These include availability of a CT scanner on request, the logistics of complex procedures on the deceased, new forms of expertise, co-operation between pathologist and radiologist, and financing.

[Pathology also subject to RCTs]. / Ook pathologie ontkomt niet aan RCT's.

Pathology is a diagnostic field and pathologists do not treat patients. It would at first seem that randomised controlled trials (RCTs) are not an option in this field. However, pathology is often the gold standard for diagnostics in RCTs and guidelines. With the arrival of new techniques in pathology diagnostics, particularly molecular techniques, it seems that more objective data can be collected. An RCT recently studied the effect of an electronic reminder for further diagnostics of Lynch syndrome, a hereditary disorder that the pathologist can detect by testing microsatellite instability. Studies to make pathology reporting more evidence-based are also very likely. Even the role of pathology in the diagnosis and treatment of patients needs to be made more verifiable.

Analysis of the relative deformation of lung lobes before and after surgery in patients with NSCLC.

An accurate assessment of the extent of the tumor is critical for successful local treatment of lung cancer by surgery and/or radiotherapy. Guidelines to establish the extent of treatment margins may be derived from correlation studies between pre-treatment imaging and histopathology. Deformations occur, however, between in-vivo CT imaging and ex-vivo pathology due to the softness of lung tissue and pathology processing. The first aim of this study was to quantify these deformations in tissue around non-small cell lung cancer. The second aim was to explore factors associated with the magnitude of the deformations. The study was performed in 25 patients who underwent lobectomy after preoperative CT. Non-rigid registration was employed to evaluate tissue deformations around the gross tumor volume (GTV), taking into account potential differences in elasticity between tumor and healthy lung tissue. Tissue was found to be compacted by approximately 60% depending on circularity of the tumor and orientation of the specimen on the pathology table during processing. The deformations give rise to potential underestimation of the treatment margins in pathology studies that do not take this aspect into account.

[Clinical reasoning and decision-making in practice. A man with hip pain and fever]. / Klinisch denken en beslissen in de praktijk. Een man met pijn in de heup en koorts.

A 42-year-old man was admitted to the hospital because of pain in the left hip. On examination he was febrile at 38 degrees C and he walked with a limp. The chest, abdomen and extremities were normal. Laboratory tests showed an elevated ESR and CRP. The ANA test was positive. CT-scan of the abdomen revealed a mass in the psoas region and some dilatation of the left renal pelvis. Following the histological results of the first and second diagnostic percutaneous biopsies, the clinicians suspected idiopathic retroperitoneal fibrosis. They treated the patient with corticosteroids for a period of 4 weeks. After a short interval of improvement this treatment failed and a third biopsy was taken. Subsequently, the diagnosis of anaplastic large cell lymphoma (ALCL) was made. The patient was successfully treated with combination chemotherapy. Usually, in practice, clinical reasoning and decision-making is carried out in accordance with Bayes' theorem. But when the a priori probability of disease is unknown and the likelihood ratio of a diagnostic test unavailable, one has to combine the available 'evidence' with critical thinking, interdisciplinary communication, judgement, intuition and common sense.

Pulmonary tumours in the Netherlands: focus on temporal trends in histology and stage and on rare tumours.

BACKGROUND: Recent temporal trends in histology and stage of pulmonary tumours in the Netherlands were studied. The incidence of rare pulmonary tumours was determined. METHODS: All tumours originating from the trachea, bronchus and lung recorded in the Netherlands Cancer Registry were included. Based on ICD-O morphology codes, five major subgroups were constructed: squamous carcinoma (SC), adenocarcinoma (AC), large cell (undifferentiated) carcinoma (LC), small cell lung cancer (SCLC) and other (including uncommon tumours). RESULTS: Between 1989 and 2003, 134,894 tumours were diagnosed. In men the age-adjusted incidence of SC and SCLC decreased, AC remained stable and LC increased. In women the incidence of all subgroups increased. Since 1996, a stage shift was observed with fewer patients in stage I and more patients in stage IV at diagnosis. This stage shift occurred equally in SC, AC and LC. In SC, fewer patients presented with stage IV disease than in AC and LC (25% vs 44% and 49% in 2003, respectively). The incidence of adenosquamous carcinoma decreased from 0.6 to 0.29/100 000 (p<0.001). The incidence of carcinoid tumours, sarcomatoid carcinomas and primary pulmonary sarcomas remained stable (0.44, 0.17 and 0.08/100 000, respectively). CONCLUSION: The incidence of smoking-related tumours decreased in men (especially SC and SCLC) and increased in women (all subgroups). More patients presented with stage IV disease. The incidence of non-smoking-related uncommon tumours remained constant.

Laparoscopic resection of a symptomatic gastric diverticulum: a minimally invasive solution.

Gastric diverticula are rare and occasionally symptomatic. A sensation of fullness in the upper abdomen immediately after meals is the most common symptom. Dyspepsia and vomiting are less common. Ulceration with hemorrhage or perforation has been reported. If it is thought that complaints can be ascribed to the diverticulum and if proton pump inhibitors do not relieve symptoms, surgical resection is an option. Knowledge of the pitfalls in diagnosis and treatment of a gastric diverticulum are essential for successful and complete relief of symptoms. We report a successful laparoscopic approach as a minimally invasive solution to a symptomatic gastric diverticulum.

[Diagnostic image (210). A young woman suffering from abdominal pain]. / Diagnose in beeld (210). Een jonge vrouw met buikpijn.

A 33-year-old pregnant woman presenting with low abdominal pain was diagnosed with left-sided tubal extra-uterine pregnancy, which was surgically removed.

An unusual presentation and way to diagnose hepatocellular carcinoma.

A 67-year-old man with a history of chronic obstructive pulmonary disease (COPD) was admitted with acute progression of dyspnoea, productive cough, fever, elevated central venous pressure, oedema and liver enzyme abnormalities. Pneumonia with secondary right-sided congestive heart failure was considered. Additional abdominal ultrasound examination confirmed by a CT scan showed a mass in the inferior vena cava (VCI) extending into the right atrium. The central liver location and impaired haemostasis rendered liver biopsy impossible. An alternative approach was discussed and guided by two-dimensional transoesophageal electrocardiography accessing the right internal jugular vein, biopsies were taken from the atrial mass with histology suggesting the presence of a hepatocellular carcinoma as the cause of acute dyspnoea.

[Diagnostic image (203). A woman with hypercalcaemia and osteolytic lesions caused by primary hyperparathyroidism]. / Diagnose in beeld (203). Een vrouw met hypercalciëmie en bothaarden.

A 76-year-old woman presented with hypercalcaemia and osteolytic lesions, caused by primary hyperparathyroidism.

[Diagnostic image (179). A woman with abdominal pain and weight loss. Intestinal infection with Strongyloides stercoralis]. / Diagnose in beeld (179). Een vrouw met buikpijn en gewichtsverlies. Darminfectie met S. stercoralis.

A 40-year-old woman presented with prolonged abdominal complaints, weight loss and iron deficiency anaemia. Coloscopic biopsy revealed a nematode infestation, probably by Strongyloides stercoralis.

[Diagnostic image (220). A young man with an obstructing lung tumor]. / Diagnose in beeld (220). Een jonge man met een obstruerende longtumor.

A 31-year-old man presented with coughing and fever. Bronchoscopy and resection of the left upper lobe revealed an obstruction by a typical carcinoid.

Granular cell tumors of the tracheobronchial tree.

OBJECTIVE: To describe the population-based incidence and clinical characteristics of granular cell tumors of the tracheobronchial tree. METHODS: All newly registered tracheobronchial granular cell tumors in the Dutch Network and National Database for Pathology for 10 consecutive years (1990-1999) were identified. The histologic diagnosis was confirmed and patient demographics, management, and follow-up data were analyzed. RESULTS: Thirty-one tumors were registered in 30 patients (12 male patients and 18 female patients; mean age 51 years; range 11-84) in a population of approximately 15 million. Tracheal tumors were identified in 11 patients and bronchial tumors in 19 patients (1 patient had 2 tumors). About half of the patients were asymptomatic. In the majority of the patients (61%) the granular cell tumor was an incidental finding during workup for lung carcinoma. Tracheal granular cell tumors were more frequent in women, whereas bronchial granular cell tumors showed no sex predilection. In the lung these tumors occurred more often in the upper (10 tumors) than in the lower lobes (3 tumors). There was no preference for either side. Four patients with tracheal and 4 with bronchial granular cell tumors were treated with surgery and remain in complete remission. Four bronchial granular cell tumor patients were treated locally with neodymium/yttrium-aluminum-garnet laser or electrocautery and are in complete remission or have stable residual disease. In 3 patients no residual disease was found after biopsy. Of all granular cell tumor patients 17 received no treatment for a variety of reasons, but none of these patients died in the follow-up period because of the granular cell tumors. CONCLUSION: Tracheobronchial granular cell tumor is a benign tumor with a good prognosis. In symptomatic patients surgical intervention is the first choice of treatment, but local treatment is a reasonable option and gives successful results.

[A gastric signet ring cell carcinoma as the first expression of a breast carcinoma]. / Een zegelringcelcarcinoom van de maag als eerste uiting van een mammacarcinoom.

A 73-year-old woman presented with dull pain in the epigastric region, a rapid feeling of fullness upon eating and a weight loss of 10 kg in 6 months. Further examination showed linitis plastica due to a signet ring cell carcinoma in the stomach, multiple bone metastases, and an occult, small breast tumour. Immunohistochemical comparison of the tumours strongly suggested that all cases involved a metastasised breast carcinoma. At check-up after one year of tamoxifen treatment, the complaints had disappeared and the activity of the tumour marker had dropped. Gastric metastases from breast carcinoma are rare. Nevertheless, this possibility should be kept in mind in women presenting with malignancies of the stomach and mastopathy. Hormonal treatment and chemotherapy may result in reasonable palliation.